title: Remodeling epigenetic modifications at tumor suppressor gene promoters with bovine oocyte extract.
abstract: OBJECTIVE
  Epigenetic silencing of tumor suppressor genes by aberrant DNA methylation and histone modifications at their promoter regions plays an important role in the initiation and progression of cancer. The therapeutic effect of the widely used epigenetic drugs, including DNA methyltransferase inhibitors and histone deacetylase inhibitors, remains unsatisfactory. One important underlying factor in the ineffectiveness of these drugs is that their actions lack specificity.
  
  
  METHODS
  To investigate whether oocyte extract can be used for epigenetic re-programming of cancer cells, H460 human lung cancer cells were reversibly permeabilized and incubated with bovine oocyte extract.
  
  
  RESULTS
  Bisulfite sequencing showed that bovine oocyte extract induced significant demethylation at hypermethylated promoter CpG islands of the tumor suppressor genes RUNX3 and CDH1; however, the DNA methylation levels of repetitive sequences were not affected. Chromatin immunoprecipitation showed that bovine oocyte extract significantly reduced transcriptionally repressive histone modifications and increased transcriptionally activating histone modifications at the promoter regions of RUNX3 and CDH1. Bovine oocyte extract reactivated the expression of RUNX3 and CDH1 at both the messenger RNA and the protein levels without up-regulating the transcription of pluripotency-associated genes. At the functional level, anchorage-independent proliferation, migration and invasion of H460 cells was strongly inhibited.
  
  
  CONCLUSIONS
  These results demonstrate that bovine oocyte extract reactivates epigenetically silenced tumor suppressor genes by remodeling the epigenetic modifications at their promoter regions. Bovine oocyte extract may provide a useful tool for investigating epigenetic mechanisms in cancer and a valuable source for developing novel safe therapeutic approaches that target epigenetic alterations.
authors.affiliation: The Key Laboratory of Mammal Reproductive Biology and Biotechnology, Ministry of Education, Inner Mongolia University, Huhhot, China.
authors.forename: Zhenfei
authors.initials: Z
authors.lastname: Wang
authors.forename: Yongli
authors.initials: Y
authors.lastname: Yue
authors.forename: Pengyong
authors.initials: P
authors.lastname: Han
authors.forename: Rula
authors.initials: R
authors.lastname: Sa
authors.forename: Xiaolv
authors.initials: X
authors.lastname: Ren
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Haidong
authors.initials: H
authors.lastname: Bai
authors.forename: Haiquan
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D002457:Cell Extracts / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism; D018899:CpG Islands / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D009865:Oocytes / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D002457:Cell Extracts; D050677:Core Binding Factor Alpha 3 Subunit; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C493729:Runx3 protein, human
keywords: bovine oocyte extract; epigenetic modification; remodeling; tumor suppressor gene